ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

Endocrine Abstracts (2011) 27 OC1.8

Mutations in PROKR2 but not PROK2 are associated with congenital hypopituitarism and septo-optic dysplasia

Mark McCabe1, Louise Gregory1, Carles Gaston-Massuet2, Oualid Sbai3, Philippe Rondard3, Marija Pfeifer4, Tony Hulse5, Charles Buchanan6, Nelly Pitteloud7, Juan-Pedro Martinez-Barbera2 & Mehul Dattani1

1Clinical and Molecular Genetics Unit, Department of Endocrinology, UCL - Institute of Child Health, London, UK; 2Neural Development Unit, UCL - Institute of Child Health, London, UK; 3Institut de Genomique Fonctionelle, Montpellier, France; 4Department of Endocrinology, University Medical Centre, Ljubljana, Slovenia; 5Guy’s and St Thomas’ Hospital, London, UK; 6King’s College Hospital, London, UK; 7Endocrinology, Diabetes and Metabolism, University of Lausanne, Lausanne, Switzerland.

Introduction: Loss-of-function mutations in PROK2 and PROKR2 in humans have been associated with Kallmann syndrome (KS), characterised by the combination of hypogonadotrophic hypogonadism with anosmia, suggesting that both are critical for GnRH neuronal development.

Objective: KS has overlapping phenotypes and genotypes through FGF8 and FGFR1 with congenital hypopituitarism including septo-optic dysplasia (SOD) and thus we aimed to screen a cohort of such patients (n=421) for mutations in PROK2 and PROKR2.

Methods: Patients were screened by direct sequencing analysis with the function of any novel variants tested by intracellular Ca2+ mobilisation and stimulation of phospho-inositol turnover.

Results: No mutations in PROK2 were detected but eight patients with SOD tested positive for heterozygous PROKR2 variations; p.L173R (n=4), p.R268C (n=2), p.A51T and p.G371R (n=1 each). The former two mutations were previously described as functionally significant; p.A51T is a probable polymorphism. p.G371R is a novel sequence variant at a highly conserved residue and was absent in 480 controls; no functional compromise has been identified to date. A further patient with SOD was homozygous for p.R268C, and a tenth patient with combined pituitary hormone deficiency presented with the functionally significant p.R85L mutation in heterozygosity. Patients presented with hormone phenotypes ranging from isolated GHD to panhypopituitarism including diabetes insipidus. Other features included gastrointestinal dysmotility (n=1), schizencephaly (n=1) and seizures (n=2). Conversely, the unaffected, healthy mother of one of our SOD patients heterozygous for the functionally significant p.L173R, was homozygous for the same change. This implies a digenicity/oligogenicity in the aetiology of SOD, and may suggest the presence of genetic modifiers which are protective. Our data reveal apparent similarities in heterozygous and homozygous phenotypes across the PROKR2 protein with variability in penetrance, and raise questions about the accepted role of PROKR2 in KS.

Conclusion: PROKR2 appears to be more frequently implicated in SOD than any of the previously described genes, and may reflect an overlap between KS and SOD; however further work is required to fully understand the role of PROKR2 in these disorders.